The invention relates to the use of bissulfonamides and their physiologically tolerated salts and physiologically functional derivatives for producing medicines for the prevention and treatment of hyperlipidemia and arteriosclerotic disorders.
U.S. Pat. No. 3,876,632 describes bissulfonamides as antihypertensives.
The invention was based on the object of providing compounds which display a therapeutically utilizable hypolipidemic effect.
The invention therefore relates to the use of compounds of formula I 
in which:
X, R1, and R2 are, independently of one another, NR6R7, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or tetrahydropyridinyl, in which each ring is optionally substituted independently of one another by phenyl, (C1-C6)-alkyl-phenyl, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O-phenyl, S-phenyl, (CO)xe2x80x94(C1-C6)-alkyl, or (CO)-phenyl, where the phenyl substituent is unsubstituted or mono- or disubstituted independently of one another by F, Cl, Br, OH, CF3, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, CONH(C3-C6)cycloalkyl, NH2, NHxe2x80x94COxe2x80x94(C1-C6)-alkyl, or NHxe2x80x94CO-phenyl;
R6 and R7 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl, Oxe2x80x94(C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, (C1-C6)-alkyl-O-phenyl, CHO, CO-phenyl, or (CH2)nxe2x80x94Ar, where n is optionally the integer 0, 1, 2, 3, 4, 5, or 6, and Ar is chosen from phenyl, biphenylyl, 1- or 2-naphthyl, 1- or 2-tetrahydrofuranyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4-, or 5-thiazolyl, 2-, 4-, or 5-oxazolyl, 1-pyrazolyl, 3-, 4-, or 5-isoxazolyl, (C3-C6)-cycloalkyl, piperidinyl, pyrrolidinyl, 2- or 3-pyrrolyl, 2- or 3-pyridazinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, 2-(1,3,5-triazinyl), 2-, 3-, or 4-morpholinyl, 2- or 5-benzimidazolyl, 2-benzothiazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl, indol-5-yl, or N-methyl-imidazol-2-, -4-, or -5-yl, and Ar is optionally mono- or disubstituted independently of one another by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94CH2xe2x80x94O, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, CONH(C3-C6)cycloalkyl, NH2, NHxe2x80x94COxe2x80x94(C1-C6)-alkyl, NHxe2x80x94CO-phenyl, pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, (CH2)n-phenyl, Oxe2x80x94(CH2)n-phenyl, Sxe2x80x94(CH2)n-phenyl, or SO2xe2x80x94(CH2)n-phenyl, where n is the integer 0, 1, 2, or 3;
or a physiologically tolerated salt or a physiologically functional derivative thereof for producing a medicine for the prevention and treatment of hyperlipidemia.
It is preferred to use compounds of formula I in which one or more radical(s) has or have the following meaning:
R1 is NR6R7, pyrrolidinyl, piperidinyl, piperazinyl, or tetrahydropyridinyl, in which each ring is optionally substituted independently of one another by phenyl, (C1-C6)-alkyl-phenyl, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O-phenyl, S-phenyl, (CO)xe2x80x94(C1-C6)-alkyl, or (CO)-phenyl, where the phenyl substituent is unsubstituted or mono- or disubstituted independently of one another by F, Cl, Br, CF3, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)-alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, NH2, NHxe2x80x94COxe2x80x94(C1-C6)-alkyl, or NHxe2x80x94CO-phenyl;
R6 and R7 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, or (CH2)nxe2x80x94Ar, where n is optionally the integer 0,1, 2, 3, 4, 5, or 6, and Ar is chosen from phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2-, 4-, or 5-thiazolyl, 2-, 4-, or 5-oxazolyl, 3- or 5-isoxazolyl, (C3-C6)-cycloalkyl, piperidinyl, pyrrolidinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, or 4-morpholinyl, 2- or 5-benzimidazolyl, 2-benzothiazolyl, indol-3-yl, or indol-5-yl, and Ar is optionally mono- or disubstituted independently of one another by F. Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, NH2, NHxe2x80x94CO-phenyl, (CH2)n-phenyl, Oxe2x80x94(CH2)n-phenyl, or Sxe2x80x94(CH2)n-phenyl, where n is the integer 0, 1, 2, or 3;
R2 is NR8R9 or piperazinyl, in which piperazinyl is optionally substituted independently of one another by (C1-C6)-alkyl-phenyl, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O-phenyl, S-phenyl, (CO)xe2x80x94(C1-C6)-alkyl, or (CO)-phenyl;
R8 and R9 are, independently of one another, H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, or (CH2)nxe2x80x94Ar, where n is the integer 0, 1, 2, 3, 4, 5, or 6, and Ar is chosen from phenyl, 2-, 3-, or 4-pyridyl, piperidinyl, pyrrolidinyl, or morpholinyl;
X is NR10R11, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, in which each ring is optionally substituted independently of one another by phenyl, (C1-C6)alkyl-phenyl, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, O-phenyl, S-phenyl, (CO)xe2x80x94(C1-C6)-alkyl, or (CO)-phenyl, where the phenyl substituent is unsubstituted or mono- or disubstituted independently of one another by F, Cl, Br, CF3, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COOH, COO(C1-C6)-alkyl, COO(C3-C6)cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, NH2, NHxe2x80x94COxe2x80x94(C1-C6)-alkyl, or NHxe2x80x94CO-phenyl;
R10 and R11 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, CO-phenyl, or (CH2)nxe2x80x94Ar, where n is the integer 0, 1, 2, 3, 4, 5, or 6, and Ar is chosen from phenyl, biphenylyl, 1- or 2-naphthyl, 1- or 2-tetrahydrofuranyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4-, or 5-thiazolyl, 2-, 4-, or 5-oxazolyl, 3- or 5-isoxazolyl, piperidinyl, pyrrolidinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, or 4-morpholinyl, or 2-benzothiazolyl, and Ar is optionally mono- or disubstituted independently of one another by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, Sxe2x80x94(C1-C6)-alkyl, SOxe2x80x94(C1-C6)-alkyl, SO2xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, NHxe2x80x94COxe2x80x94(C1-C6)-alkyl, NHxe2x80x94CO-phenyl, or (CH2)n-phenyl where n is the integer 0, 1, 2, or 3;
or a physiologically tolerated salt or a physiologically functional derivative thereof for producing a medicine for the prevention and treatment of hyperlipidemia.
It is particularly preferred to use compounds of formula I in which one or more radical(s) has or have the following meaning:
R1 is NR6R7, piperidinyl, piperazinyl, or tetrahydropyridinyl, in which each ring is optionally substituted independently of one another by phenyl or (C1-C6)-alkyl-phenyl;
R6 and R7 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkyl-NHxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, or (CH2)nxe2x80x94Ar, where n is the integer 0, 1, 2, 3, 4, 5, or 6, and Ar is chosen from phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, (C3-C6)-cycloalkyl, piperidinyl, pyrrolidinyl, 2-, 4-, or 5-pyrimidinyl, or 2-, 3-, or 4-morpholinyl, and Ar is optionally mono- or disubstituted independently of one another by F, Cl, Br, OH, CF3, NO2, CN, OCF3, Oxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl, or NH2;
R2 is NR8R9 or piperazinyl, in which piperazinyl is optionally substituted by (C1-C6)-alkyl;
R8 and R9 are, independently of one another, H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, COxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, or (CH2)nxe2x80x94Ar, where n is the integer 0, 1, 2, 3, 4, 5, or 6, and Ar is chosen from phenyl, 2-, 3-, or 4-pyridyl, piperidinyl, pyrrolidinyl, or morpholinyl;
X is NR10R11, pyrrolidinyl, piperidinyl, or morpholinyl, in which each ring is optionally substituted independently of one another by phenyl or (C1-C6)-alkyl-phenyl;
R10 and R11 are, independently of one another, H, (C1-C6)-alkyl, (C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkyl-NHxe2x80x94(C1-C6)-alkyl, (C1-C6)-alkyl-Nxe2x80x94[(C1-C6)-alkyl]2, (CH2)nxe2x80x94Ar, where n is the integer 0, 1, 2, 3, 4, 5, or 6, and Ar is chosen from phenyl or 2- or 3-thienyl;
or a physiologically tolerated salt thereof for producing a medicine for the prevention and treatment of hyperlipidemia.
The invention relates to the use of compounds of formula I in the form of their racemates, racemic mixtures, and pure enantiomers, and to their diastereomers and mixtures thereof.
The alkyl, alkenyl, and alkynyl radicals in the substituents X, R1, and R2 may be either straight-chain or branched.
The term xe2x80x9csubstitutedxe2x80x9d means mono- or polysubstitution unless otherwise indicated.
Pharmaceutically acceptable salts are particularly suitable for medical applications because their solubility in water is higher than the initial or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of compounds of formula I are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfamic, and sulfuric acids, and organic acids such as, for example, acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric, and trifluoroacetic acids. The chloride salt and the tartaric acid salt are particularly preferably used for medical purposes. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts).
Salts with a pharmaceutically unacceptable anion likewise fall within the scope of the invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic, for example, in vitro, applications.
The term xe2x80x9cphysiologically functional derivativexe2x80x9d used herein refers to any physiologically tolerated derivative of a compound according to the invention, for example, an ester, which is able on administration to a mammal such as, for example, a human, to form (directly or indirectly) such a compound or an active metabolite thereof.
A further aspect of this invention is the use of prodrugs of compounds of formula I. Such prodrugs can be metabolized in vivo to a compound of formula I. These prodrugs may themselves be active or not.
Compounds of formula I may also exist in various polymorphous forms, for example, as amorphous and crystalline polymorphous forms. All polymorphous forms of compounds of formula I lie within the scope of the invention and are a further aspect of the invention.
All references hereinafter to xe2x80x9ccompound(s) of formula Ixe2x80x9d refer to compound(s) of formula I as described above, or the salts, solvates, or physiologically functional derivatives thereof as described herein.
The amount of a compound of formula I which is necessary to achieve the desired biological effect depends on a number of factors, for example, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of body weight, for example, 3 to 10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg/kg to 1 mg/kg, which can most suitably be administered as infusion of from 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. It is thus possible for ampoules for injections to contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, tablets or capsules, to contain, for example, from 1 mg to 1000 mg, typically from 10 mg to 600 mg. In the case of pharmaceutically acceptable salts, the aforementioned weight data are based on the weight of the salt of the compound of formula I. For the prophylaxis or therapy of the abovementioned conditions, compounds of formula I can be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not hazardous for the patient""s health. The carrier may be a solid or a liquid or both, and is preferably formulated with the compound as single dose, for example, as tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Further pharmaceutically active substances may likewise be present, including other compounds of formula I. The pharmaceutical compositions according to the invention can be produced by one of the known pharmaceutical methods which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
Pharmaceutical compositions according to the invention are those suitable for oral, rectal, topical, peroral (for example sublingual), and parenteral (for example, subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable mode of administration in each individual case depends on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated slow-release formulations also lie within the scope of the invention. Formulations resistant to acid and gastric fluid are preferred. Suitable coatings resistant to gastric fluid comprise cellulose acetate phthalate, polyvinyl acetate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate.
Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets, or tablets, each of which contain a defined amount of the compound of formula l; as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. In general, the compositions are produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tabletting the compound in free-flowing form, such as, for example, a powder or granules, where appropriate mixed with a binder, lubricant, inert diluent, and/or a (plurality of) surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine.
Pharmaceutical compositions suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular, or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions according to the invention generally contain from about 0.1% to about 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical application to the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol, or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from about 0.1% to about 15% by weight of the composition, for example from about 0.5% to about 2%.
Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient""s epidermis. Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable active ingredient concentration is about 1% to about 35%, preferably about 3% to about 15%. As a special possibility, the active ingredient can be released as described, for example, in Pharmaceutical Research, 2(6) (1986) 318, by electrotransport or iontophoresis.
The following preparations serve to illustrate the invention without restricting it, however.